RESUMEN
SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages, and tissues was not reduced with baricitinib. Type I interferon (IFN) antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection.
Asunto(s)
Antiinflamatorios/administración & dosificación , Azetidinas/administración & dosificación , Tratamiento Farmacológico de COVID-19 , COVID-19/inmunología , Macaca mulatta , Infiltración Neutrófila/efectos de los fármacos , Purinas/administración & dosificación , Pirazoles/administración & dosificación , Sulfonamidas/administración & dosificación , Animales , COVID-19/fisiopatología , Muerte Celular/efectos de los fármacos , Degranulación de la Célula/efectos de los fármacos , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Quinasas Janus/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Activación de Linfocitos/efectos de los fármacos , Macrófagos Alveolares/inmunología , SARS-CoV-2/fisiología , Índice de Severidad de la Enfermedad , Linfocitos T/inmunología , Replicación Viral/efectos de los fármacosRESUMEN
Sickle cell disease (SCD) is caused by a point mutation in the ß-globin gene that creates hemoglobin S (HbS). Upon deoxygenation, HbS forms long polymers that distort the shape of red blood cells, causing hemolysis and vaso-occlusion. Voxelotor inhibits HbS polymerization, the root cause of SCD complications. To view this Bench to Bedside, open or download the PDF.
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Anemia de Células Falciformes/genética , Benzaldehídos/uso terapéutico , Hemoglobina Falciforme/antagonistas & inhibidores , Pirazinas/uso terapéutico , Pirazoles/uso terapéutico , Globinas beta/genética , Anemia de Células Falciformes/epidemiología , Hemoglobina Falciforme/genética , Humanos , Mutación Puntual/genética , Polimerizacion/efectos de los fármacosRESUMEN
TRIKAFTA is the third drug approved by the FDA that rescues defects caused by the major mutation F508del. It is superior to its predecessors that were approved for patients who are homozygous for F508del because TRIKAFTA is also effective in CF patients who harbor only one copy of this mutation.
Asunto(s)
Aminofenoles/farmacología , Benzodioxoles/farmacología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Indoles/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Quinolinas/farmacología , Combinación de Medicamentos , Heterocigoto , Humanos , MutaciónRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of the six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF) by PDAC cells to promote tumor innervation. Consistent with this, exSer-dependent PDAC tumors grew slower and displayed enhanced innervation in mice on a Ser/Gly-free diet. Blockade of compensatory neuronal innervation using LOXO-101, a Trk-NGF inhibitor, further decreased PDAC tumor growth. Our data indicate that axonal-cancer metabolic crosstalk is a critical adaptation to support PDAC growth in nutrient poor environments.
Asunto(s)
Neuronas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Biosíntesis de Proteínas , Serina/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Animales , Axones/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular , Codón/genética , Femenino , Glicina/metabolismo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Mitocondrias/metabolismo , Tejido Nervioso/patología , Consumo de Oxígeno , Neoplasias Pancreáticas/patología , Pirazoles , Pirimidinas , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN de Transferencia/genética , RatasRESUMEN
Larotrectinib is a small-molecule kinase inhibitor that targets NTRK fusions that occur in multiple types of cancer. Its FDA approval represents the first instance of a treatment indication being designated "tumor-agnostic" from the outset, being based on actionable genomic insights. To view this Bench to Bedside, open or download the PDF.
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Pirazoles/metabolismo , Pirazoles/farmacología , Pirimidinas/metabolismo , Pirimidinas/farmacología , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , Humanos , Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/agonistas , Receptor trkB/metabolismoRESUMEN
Vibrio cholerae uses a quorum-sensing (QS) system composed of the autoinducer 3,5-dimethylpyrazin-2-ol (DPO) and receptor VqmA (VqmAVc), which together repress genes for virulence and biofilm formation. vqmA genes exist in Vibrio and in one vibriophage, VP882. Phage-encoded VqmA (VqmAPhage) binds to host-produced DPO, launching the phage lysis program via an antirepressor that inactivates the phage repressor by sequestration. The antirepressor interferes with repressors from related phages. Like phage VP882, these phages encode DNA-binding proteins and partner antirepressors, suggesting that they, too, integrate host-derived information into their lysis-lysogeny decisions. VqmAPhage activates the host VqmAVc regulon, whereas VqmAVc cannot induce phage-mediated lysis, suggesting an asymmetry whereby the phage influences host QS while enacting its own lytic-lysogeny program without interference. We reprogram phages to activate lysis in response to user-defined cues. Our work shows that a phage, causing bacterial infections, and V. cholerae, causing human infections, rely on the same signal molecule for pathogenesis.
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Lisogenia/fisiología , Pirazoles/metabolismo , Percepción de Quorum/fisiología , Bacteriófagos/metabolismo , Biopelículas , Proteínas de Unión al ADN/metabolismo , Regulación Bacteriana de la Expresión Génica/genética , Percepción de Quorum/genética , Vibrio/metabolismo , Vibrio cholerae/metabolismo , Vibrio cholerae/fisiología , Virulencia , Latencia del VirusRESUMEN
Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.
Asunto(s)
Antagonistas de Receptores de Cannabinoides/química , Morfolinas/química , Pirazoles/química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/química , Sitios de Unión , Cannabinoides/farmacología , Cannabis/química , Cristalografía por Rayos X , Dronabinol/farmacología , Endocannabinoides/farmacología , Humanos , Ligandos , Morfolinas/síntesis química , Unión Proteica , Conformación Proteica en Hélice alfa , Pirazoles/síntesis químicaRESUMEN
Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1-5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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COVID-19 , Proteínas Activadoras de GTPasa , Estudio de Asociación del Genoma Completo , Factores de Intercambio de Guanina Nucleótido , Interacciones Microbiota-Huesped , SARS-CoV-2 , Alelos , Animales , COVID-19/complicaciones , COVID-19/genética , COVID-19/inmunología , COVID-19/fisiopatología , Modelos Animales de Enfermedad , Proteínas Activadoras de GTPasa/antagonistas & inhibidores , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Predisposición Genética a la Enfermedad , Factores de Intercambio de Guanina Nucleótido/antagonistas & inhibidores , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Interacciones Microbiota-Huesped/genética , Interacciones Microbiota-Huesped/inmunología , Humanos , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Japón , Pulmón/patología , Macrófagos , Mesocricetus , Persona de Mediana Edad , Neumonía/complicaciones , Pirazoles/farmacología , RNA-Seq , SARS-CoV-2/patogenicidad , Carga Viral , Pérdida de PesoRESUMEN
While effective anti-cancer drugs targeting the CHK1 kinase are advancing in the clinic, drug resistance is rapidly emerging. Here, we demonstrate that CRISPR-mediated knockout of the little-known gene FAM122A/PABIR1 confers cellular resistance to CHK1 inhibitors (CHK1is) and cross-resistance to ATR inhibitors. Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. The resulting increase in WEE1 protein expression reduces replication stress, activates the G2/M checkpoint, and confers cellular resistance to CHK1is. Interestingly, in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. A combination of a CHK1i plus a WEE1 inhibitor can overcome CHK1i resistance of these tumor cells, thereby enhancing anti-cancer activity. The FAM122A expression level in a tumor cell can serve as a useful biomarker for predicting CHK1i sensitivity or resistance.
Asunto(s)
Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfoproteínas/metabolismo , Pirazinas/farmacología , Pirazoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Daño del ADN/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intracelular/fisiología , Proteínas Nucleares/metabolismo , Fosfoproteínas/fisiología , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Tirosina Quinasas/genética , Pirazinas/metabolismo , Pirazoles/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The emergence of drug resistance is a major obstacle for the success of targeted therapy in melanoma. Additionally, conventional chemotherapy has not been effective as drug-resistant cells escape lethal DNA damage effects by inducing growth arrest commonly referred to as cellular dormancy. We present a therapeutic strategy termed "targeted chemotherapy" by depleting protein phosphatase 2A (PP2A) or its inhibition using a small molecule inhibitor (1,10-phenanthroline-5,6-dione [phendione]) in drug-resistant melanoma. Targeted chemotherapy induces the DNA damage response without causing DNA breaks or allowing cellular dormancy. Phendione treatment reduces tumor growth of BRAFV600E-driven melanoma patient-derived xenografts (PDX) and diminishes growth of NRASQ61R-driven melanoma, a cancer with no effective therapy. Remarkably, phendione treatment inhibits the acquisition of resistance to BRAF inhibition in BRAFV600E PDX highlighting its effectiveness in combating the advent of drug resistance.
Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Melanoma/tratamiento farmacológico , Pirazoles/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Humanos , Melanoma/enzimología , Melanoma/fisiopatología , Proteína Fosfatasa 2/antagonistas & inhibidoresRESUMEN
BACKGROUND: Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy. METHODS: In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours. RESULTS: A total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported. CONCLUSIONS: Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.).
Asunto(s)
Estudios Cruzados , Humanos , Femenino , Método Doble Ciego , Masculino , Adulto , Administración Oral , Persona de Mediana Edad , Angioedemas Hereditarios/tratamiento farmacológico , Adolescente , Adulto Joven , Anciano , Angioedema Hereditario Tipos I y II/tratamiento farmacológico , PirazolesRESUMEN
BACKGROUND: The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown. METHODS: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles. RESULTS: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively. CONCLUSIONS: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Lenalidomida , Linfoma de Células B Grandes Difuso , Piperidinas , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adenina/análogos & derivados , Adenina/efectos adversos , Adenina/uso terapéutico , Adenina/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Lenalidomida/efectos adversos , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Terapia Molecular Dirigida , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Piperidinas/administración & dosificación , Prednisona/efectos adversos , Prednisona/administración & dosificación , Prednisona/uso terapéutico , Supervivencia sin Progresión , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Pirazoles/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Recurrencia , Sulfonamidas/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéuticoRESUMEN
BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Asunto(s)
Proteína AIRE , Interferón gamma , Inhibidores de las Cinasas Janus , Poliendocrinopatías Autoinmunes , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Proteína AIRE/deficiencia , Proteína AIRE/genética , Proteína AIRE/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Quimiocina CXCL9/genética , Interferón gamma/genética , Interferón gamma/inmunología , Inhibidores de las Cinasas Janus/uso terapéutico , Ratones Noqueados , Nitrilos/uso terapéutico , Poliendocrinopatías Autoinmunes/genética , Poliendocrinopatías Autoinmunes/tratamiento farmacológico , Poliendocrinopatías Autoinmunes/inmunología , Pirazoles/uso terapéutico , Pirazoles/farmacología , Pirimidinas/uso terapéutico , Linfocitos T/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Proyectos Piloto , Modelos Animales de Enfermedad , Niño , Adolescente , Persona de Mediana EdadRESUMEN
The triumph of personalized cancer therapeutics in recent years is prompting some oncologists to rethink clinical trial design; other researchers have different priorities for trial reform.
Asunto(s)
Ensayos Clínicos como Asunto , Neoplasias/tratamiento farmacológico , Medicina de Precisión , Crizotinib , Estudio de Asociación del Genoma Completo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer (NSCLC)1. However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC2. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1-LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1-LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1-LTK fusion as a target in NSCLC that could be treated with lorlatinib.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Transformación Celular Neoplásica/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas Receptoras/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Transformación Celular Neoplásica/efectos de los fármacos , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 15/genética , Humanos , Lactamas/farmacología , Lactamas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Desnudos , Pirazoles/farmacología , Pirazoles/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and squamous-cell carcinoma. The cause is unknown, and mortality is high. METHODS: We evaluated four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM. Genomic sequencing independently identified three heterozygous variants in a specific region of the gene that encodes signal transducer and activator of transcription 4 (STAT4). Primary skin fibroblast and cell-line assays were used to define the functional nature of the genetic defect. We also assayed gene expression using single-cell RNA sequencing of peripheral-blood mononuclear cells to identify inflammatory pathways that may be affected in DPM and that may respond to therapy. RESULTS: Genome sequencing revealed three novel heterozygous missense gain-of-function variants in STAT4. In vitro, primary skin fibroblasts showed enhanced interleukin-6 secretion, with impaired wound healing, contraction of the collagen matrix, and matrix secretion. Inhibition of Janus kinase (JAK)-STAT signaling with ruxolitinib led to improvement in the hyperinflammatory fibroblast phenotype in vitro and resolution of inflammatory markers and clinical symptoms in treated patients, without adverse effects. Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that were appropriately modified through JAK inhibition. CONCLUSIONS: Gain-of-function variants in STAT4 caused DPM in the families that we studied. The JAK inhibitor ruxolitinib attenuated the dermatologic and inflammatory phenotype in vitro and in the affected family members. (Funded by the American Academy of Allergy, Asthma, and Immunology Foundation and others.).
Asunto(s)
Enfermedades Autoinmunes , Fármacos Dermatológicos , Quinasas Janus , Esclerodermia Sistémica , Quinasas Janus/antagonistas & inhibidores , Nitrilos , Pirazoles/uso terapéutico , Pirazoles/farmacología , Pirimidinas , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/genética , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/genética , Mutación Missense , Mutación con Ganancia de Función , Fármacos Dermatológicos/uso terapéutico , Antiinflamatorios/uso terapéuticoRESUMEN
Signaling via the T cell antigen receptor (TCR) is initiated by Src-family kinases (SFKs). To understand how the kinase Csk, a negative regulator of SFKs, controls the basal state and the initiation of TCR signaling, we generated mice that express a Csk variant sensitive to an analog of the common kinase inhibitor PP1 (Csk(AS)). Inhibition of Csk(AS) in thymocytes, without engagement of the TCR, induced potent activation of SFKs and proximal TCR signaling up to phospholipase C-γ1 (PLC-γ1). Unexpectedly, increases in inositol phosphates, intracellular calcium and phosphorylation of the kinase Erk were impaired. Altering the actin cytoskeleton pharmacologically or providing costimulation via CD28 'rescued' those defects. Thus, Csk has a critical role in preventing TCR signaling. However, our studies also revealed a requirement for actin remodeling, initiated by costimulation, for full TCR signaling.
Asunto(s)
Actinas/metabolismo , Citoesqueleto/metabolismo , Proteínas Mutantes/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Timocitos/inmunología , Familia-src Quinasas/metabolismo , Animales , Antígenos CD28/inmunología , Proteína Tirosina Quinasa CSK , Células Cultivadas , Citocalasina D/administración & dosificación , Citoesqueleto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Mutantes/genética , Polimerizacion/efectos de los fármacos , Ingeniería de Proteínas , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Timocitos/efectos de los fármacos , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/genéticaRESUMEN
ABSTRACT: Nonmelanoma skin cancers (NMSCs) in ruxolitinib-treated patients with myeloproliferative neoplasms behave aggressively, with adverse features and high recurrence. In our cohort, mortality from metastatic NMSC exceeded that from myelofibrosis. Vigilant skin assessment, counseling on NMSC risks, and prospective ruxolitinib-NMSC studies are crucial.
Asunto(s)
Trastornos Mieloproliferativos , Pirazoles , Pirimidinas , Neoplasias Cutáneas , Humanos , Estudios Prospectivos , Trastornos Mieloproliferativos/tratamiento farmacológico , Nitrilos , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
ABSTRACT: In September 2023, the US Food and Drug Administration approved momelotinib for the treatment of myelofibrosis (MF) with anemia, marking the fourth US regulatory approval of a Janus kinase inhibitor for MF. A positive opinion from the European Medicines Agency followed in November 2023. Momelotinib's ability to address splenomegaly, symptoms, and anemia, including in patients with thrombocytopenia (with platelet counts of ≥25 × 109/L), the ease of switching from ruxolitinib, and good tolerability uniquely position it to substantially impact the MF treatment landscape.
Asunto(s)
Benzamidas , Mielofibrosis Primaria , Pirimidinas , Mielofibrosis Primaria/tratamiento farmacológico , Humanos , Pirimidinas/uso terapéutico , Benzamidas/uso terapéutico , Nitrilos/uso terapéutico , Pirazoles/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
ABSTRACT: Mutations in MYD88 (95%-97%) and CXCR4 (30%-40%) are common in Waldenström macroglobulinemia (WM). TP53 is altered in 20% to 30% of patients with WM, particularly those previously treated. Mutated MYD88 activates hematopoietic cell kinase that drives Bruton tyrosine kinase (BTK) prosurvival signaling. Both nonsense and frameshift CXCR4 mutations occur in WM. Nonsense variants show greater resistance to BTK inhibitors. Covalent BTK inhibitors (cBTKi) produce major responses in 70% to 80% of patients with WM. MYD88 and CXCR4 mutation status can affect time to major response, depth of response, and/or progression-free survival (PFS) in patients with WM treated with cBTKi. The cBTKi zanubrutinib shows greater response activity and/or improved PFS in patients with WM with wild-type MYD88, mutated CXCR4, or altered TP53. Risks for adverse events, including atrial fibrillation, bleeding diathesis, and neutropenia can differ based on which BTKi is used in WM. Intolerance is also common with cBTKi, and dose reduction or switchover to another cBTKi can be considered. For patients with acquired resistance to cBTKis, newer options include pirtobrutinib or venetoclax. Combinations of BTKis with chemoimmunotherapy, CXCR4, and BCL2 antagonists are discussed. Algorithms for positioning BTKis in treatment naïve or previously treated patients with WM, based on genomics, disease characteristics, and comorbidities, are presented.